Viruses and Liver Cancer

173 Pages·2002·2.929 MB·1-176\173

by  Edward Tabor (Eds.)

vii
Preface
Hepatocellular carcinoma (HCC) is the end result of a long and complicated disease
process that usually begins at the time of onset of chronic infection by the hepatitis B
or C virus. Thus, the "hepatocellar carcinoma disease process" should be considered
a continuum, a process that often begins in early childhood (for cases associated with
the hepatitis B virus) or in mid-life (for cases associated with the hepatitis C virus),
that damages the liver, and that ends as cancer.
This continuum usually extends over many decades. Hepatitis B virus (HBV)
infections usually must be acquired before, during, or soon after birth in order for
HBV-associated HCC to develop in adulthood. Patients who acquire HBV infec-
tions as adults almost never develop HBV-associated HCC. In contrast, patients who
develop hepatitis C virus (HCV)-associated HCC often acquire those HCV infec-
tions after age 40 years, and the HCC often develops 20 or more years thereafter.
HBV-associated HCC is now preventable by vaccination against HBV. In
addition, antiviral drugs can be used to eliminate detectable viremia in established
cases of chronic HBV infection or chronic HCV infection. It si hoped that such
measures will prevent the development of HCC. While there si early evidence from
vaccine trials to indicate that the hepatitis B vaccine can prevent HCC, definitive
clinical trials to evaluate the effect of antiviral treatment of HBV and HCV infections
on HCC incidence have not yet been reported.
The impact of recent research on HCC will be widespread. In some parts of the
world, HCC is one of the most common tumors in adult men. In addition, there si
evidence that the incidence of this cancer has doubled in the past 51 to 02 years in
many countries, and the incidence has doubled repeatedly every 02 years for the past
half century in Japan. Our increasing knowledge of the disease process will result in
measures that can interrupt a serious and growing public health problem.
In this book, Viruses and Liver Cancer, leading researchers on HCC from China,
France, Japan, South Africa, Spain, Taiwan, and the USA report on the latest
advances in the molecular biology, epidemiology, prevention, and treatment of HCC.
Their contributions to this book provide a useful overview for readers in other fields
who wish to learn about this disease, and they provide a useful reference text for
investigators working on HCC.
The Editor
sesuriV and Liver Cancer
.E Tabor )rotide(
© 2002 reiveslE ecneicS .V.B llA sthgir devreser
The epidemiology of primary liver cancer: global
epidemiology
F.X. Bosch, .J Ribes
Servei d'Epidemiologia i Registre del Chncer, Institut lglataC d'Oncologia, L'Hospitalet de ,tagerbolL
Barcelona, Spain
Abbreviations: AAIRs, Age Adjusted Incidence Rates; AAMRs, Age Adjusted Mortality
Rates; AF %, Attributable Fraction percent; C.I., Confidence Interval; HBV, hepatitis B
virus; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; anti-HCV, antibody to
hepatitis C virus; ICD-8, International Classification of Diseases 8th edition; ICD-9, Inter-
national Classification of Diseases 9th edition; OR, Odds Ratio; SEER, Surveillance,
Epidemiology, and End Results (National Cancer Institute); WHO, World Health
Organization.
Introduction
The epidemiology of hepatocellular carcinoma can be best evaluated through the use
of national cancer registries, which generally list this tumor among those designated
"primary liver cancer". Therefore the term "primary liver cancer" will be used
throughout this chapter, which is based largely on data from such national cancer
registries.
Primary liver cancer remains one of the most common malignancies in the world
and the most common in men in many developing countries. It is also the first human
cancer amenable to prevention in some cases using hepatitis B virus (HBV) vaccine.
It has been estimated that some 564,000 new cases of primary liver cancer occurred
woxldwide during the year 2000. The geographic areas at highest risk are located in
eastern Asia, middle Africa and some countries of western Africa. Low-risk areas
include northern Europe, Australia, New Zealand, and the Caucasian populations of
North America and South America. In high risk countries, incidence rates are
typically two to three times higher than in low risk countries.
The incidence of primary liver cancer
Significant variations in the incidence of primary liver cancer have been shown
among different populations living in the same geographic areas and between native
and migrant populations in the same geographic areas. The variability of primary
liver cancer incidence rates between countries and within countries is largely
explained by the distribution of HBV and HCV. The attributable risk estimates for
Table 1
Age-adjusted incidence rates of primary liver cancer per 000,001 population by geographic area.
Estimates for the year 0002 .1
Geographic area Men Women Sex Ratio c
No. AAIRs No. AAIRs
World 463893 79.41 279561 15.5 27.2
Developed countries 07237 17.8 08633 68.2 50.3
Developing countries 801523 34.71 892231 77.6 75.2
Africa
Eastern Africa 6748 44.41 3004 20.6 04.2
Middle Africa 2766 12.42 0824 89.21 68.1
Northern Africa 3852 59.4 7751 86.2 58.1
Southern Africa 938 61.6 753 70.2 89.2
Western Africa 6978 15.31 5024 61.6 91.2
Asia
Eastern Asia 725172 64.53 909101 66.21 08.2
South-Eastern Asia 06433 53.81 06611 07.5 22.3
Southern Central Asia 77641 77.2 5508 54.1 19.1
Western Asia 1453 06.5 7141 60.2 27.2
Pacific Islands a 634 3.81 142 4.9 59.1
Europe
Eastern Europe 86501 08.5 0637 55.2 72.2
Northern Europe 5191 16.2 6231 93.1 88.1
Southern Europe 74611 48.9 1755 54.3 58.2
Western Europe 8148 58.5 0903 16.1 36.3
America
The Caribbean 2821 85.7 797 71.4 28.1
Central America 878 60.2 687 46.1 62.1
Southern America 0116 08.4 7955 86.3 03.1
Northern America b 2028 11.4 3334 86.1 54.2
Australia & New Zealand 145 06.3 212 91.1 30.3
aMelanesia, Micronesia and Polynesia; bUnited States of America & Canada; cSex ratio: men
AAIRs/women AAIRs; AAIRs: Age Adjusted Incidence Rates.
the combined effects of these infections account for well over 80% of primary liver
cancer cases worldwide. Other documented risk factors for primary liver cancer such
as alcohol consumption, cigarette smoking, aflatoxin in the diet, and use of oral
contraceptives also may explain some variations in incidence observed.
In the year 2000 it was estimated that approximately 564,000 new cases of primary
liver cancer occurred worldwide (398,364 in men and 165,972 in women) (Table 1).
This tumor accounts for 5.6% of all human cancers (7.5% among men and 3.5%
Table 2
Age-adjusted mortality rates of primary liver cancer per 100,000 population by geographic area. Estimates
for the year 2000 1,4.
Geographic area Men Women
No. AAMRs No. AAMRs
World 395383 14.41 169461 5.46
Developed countries 29986 8.07 75663 10.3
Developing countries 116413 68.61 503821 75.6
Africa
Eastern Africa 3138 71.41 9293 19.5
Middle Africa 9356 37.32 5914 27.21
Northern Africa 9252 58.4 7451 36.2
Southern Africa 487 5.80 633 59.1
Western Africa 0228 27.21 7293 97.5
Asia
Eastern Asia 640752 05.33 58479 90.21
South-Eastern Asia 21513 53.71 24901 5.37
Southern Central Asia 00441 27.2 4887 14.1
Western Asia 9843 15.5 8731 10.2
Pacific Islands" 704 2.71 422 8.8
Europe
Eastern Europe 24801 19.5 2418 2.76
Northern Europe 7612 68.2 0661 46.1
Southern Europe 53221 90.01 0517 4.27
Western Europe 4789 96.6 4434 90.2
America
The Caribbean 2131 7.80 468 15.4
Central America 910 41.2 028 07.1
Southern America 1306 57.4 2955 3.67
Northern America b 4558 4.20 7905 98.1
Australia & New Zealand 925 54.3 252 73.1
aMelanesia, Micronesia and Polynesia; b United States of America & Canada; AAMRs: Age Adjusted
Mortality Rates.
among women). Primary liver cancer ranks as the fifth most frequent cancer in the
world (fifth among men and eighth among women) if colon and rectal cancers are
grouped together and if mouth and pharyngeal cancers are grouped together 1
(based on analysis of reports of population-based cancer registries 2,3 and the
World Health Organization (WHO) mortality databank 4). (The incidence rates
shown in Tables 1 and 2 are age-adjusted incidence rates (AAIR) and age-adjusted
mortality rates (AAMR) and represent annual averages per 100,000 men or women.
The standard population used for the adjustment is the world standard population,
which tends to increase rates in countries with young populations and to decrease
rates in countries with older populations.)
Geographic variation in incidence
Primary liver cancer shows considerable variation in incidence within broad
geographic areas (Table 1). In eastern Asia, primary liver cancer AAIRs in males
range from a relatively low rate in Japan (29.21), to high rates in Korea (48.77) and
Mongolia (98.93). In middle Africa, rates range from low in Angola (5.77), to high in
the Congo (32.33), with intermediate rates in Cameroon (17.72), Congo Brazzaville
(13.24), and Gabon (13.01), Central African Republic (24.21), and Equatorial
Guinea (24.21). In western Africa, incidence rates range from low in Nigeria (8.20) to
high in The Gambia (39.67), Mall (34.56), and Guinea (33.15) [1]. This variability is
also observed among women. In contrast, in Australia and New Zealand, Europe,
and the Americas, there is less variability in primary liver cancer incidence rates (Fig.
1). (Haiti, however, shows primary liver cancer AAIRs similar to some areas of Asia
and Africa.)
Age and sex distribution
In most high-risk areas for primary liver cancer, such as south-east Asia and the west
coast of Africa, the incidence increases after 30 years of age and peaks at the age
interval 50 to 60 years. In fact, in these countries, primary liver cancer is not rare at
any age over 20 years. In some areas, however, a second pattern is also observed; for
instance, in Shanghai the incidence rates are low before age 60 and increase
Asia
Pacific Islands
Africa
Europe
America * Haiti (25.9)
Australia/New Zealand 4
Less Developed
More Developed
o Io o2 03 40 50 I/ 400
sRIAA
+ :ailognoM 98.9
Fig. .1 Summary estimates and range of the primary liver cancer AAIRs by geographic area and level of
development: Men, 2000 [1].
thereafter. This pattern is similar to the one usually observed in low risk areas, where
primary liver cancer incidence is a rare disease before 40 years of age.
The average age at onset of the HBV-associated primary liver cancer is around 55
years, which is 01 years younger than the average age at onset of HCV-related
primary liver cancer cases 5. In Japan, a country where HCV-related primary liver
cancer cases predominate, the incidence among men increases after 54 to 50 years of
age and reaches a peak around 56 years of age.
One possible explanation for the age-specific incidence rates is the natural history
of HBV and HCV infections. Exposure to HBV occurs at birth or soon after in most
high-risk countries, particularly in Asia, where many HBV-infected mothers have
hepatitis B "e" antigen in their serum and remain HBV-DNA positive throughout
their reproductive years 6. In high-risk areas in Africa, mother-to-child trans-
mission is less common, and child-to-child transmission predominates. In low risk
areas of the world, HBV acquisition at birth si rare and most infections with HBV or
HCV are acquired in adulthood .7
Risk factors for primary liver cancer are largely the same for both men and
women. The correlation between primary liver cancer AAIRs in men and women is
extremely high (correlation coefficient: 0.953,p < 0.001). 7. However, an excess of
primary liver cancer incidence among men compared to women has been well
documented (range of the sex ratio in the AAIRs si 4.1 to 3.3; Table .)1 In high-risk
countries, sex ratios tend to be higher, and the male excess is more pronounced
around 40-50 years of age. In populations with low incidence, the highest sex ratios
occur later, around 60-70 years of age 8. The roles of alcohol, tobacco and oral
contraceptive use as typical sex-specific risk factors could contribute to the sex ratio
pattern.
Considerations in the assessment of mortality from primary liver cancer
Coding recommendations for primary liver cancer and liver metastasis changed
between the eighth to the ninth revisions of the International Classification of
Diseases coding manual (ICD-8 and ICD-9) 9,10. In developed countries where, in
general, primary liver cancer is not frequent, the probability of incorrectly coding
liver metastasis as primary liver cancer si relatively high. In spite of such limitations of
mortality data, primary liver cancer AAMRs follow a similar pattern to primary liver
cancer incidence data (Table 2) .1
The fatality ratio (primary liver cancer AAMRs / primary liver cancer AAIRs) is
near (or greater than) ,1 indicating that most patients do not survive one year. Studies
in population-based cancer registries revealed that the five-year relative survival rate
(mortality from primary liver cancer adjusted for mortality from competing causes)
was 5% in Europe (1985-1989) 11 and 6% in North America (1983-1988) 12.
There are few differences in survival rates according to sex. In Europe, relative
survival rates were higher in young patients (< 54 years of age) and were attributed to
aggressive treatment including liver transplantation. In developing countries,
primary liver cancer is inevitably fatal.
Trends in primary liver cancer incidence and mortality
International variations in coding and registration practices for primary liver cancer
make the interpretation of long-term trends difficult. During the last two decades,
increases of primary liver cancer incidence and mortality rates have been reported in
Japan 13, France 14-16, in urban Shanghai 17, and in the UK 18. A study in the
United States covering 1976 to 1997 showed significant trends of increased incidence
for black, white and Hispanic populations 19. These results were consistent with the
most recent results from the SEER database 20. In Japan, increasing primary liver
cancer incidence and mortality have been variously attributed to increasing alcohol
consumption 21, to massive exposure of the population to HCV through blood
transfusion or contaminated needles in vaccination campaigns against tuberculosis
after World War II 22, and to intravenous drug abuse 23. Increasing trends in
primary liver cancer incidence among men have also been suggested by data in
registries in Australia, India, Israel, Canada, Italy, Spain and Finland 2,3,15,16,24.
Decreasing incidence trends have been reported in Scandinavia, parts of China, and
among certain populations of Japanese descent in the US 2,3.
The spread of HCV in some populations due to massive public health inter-
ventions under sub-optimal conditions has been reported and could contribute to
future increases in primary liver cancer incidence. In Egypt, HCV prevalence has
been estimated to be 6-9% in urban areas and 27-30% in rural parts of the Nile delta.
A carefully documented epidemiologic study traced the source of these HCV infec-
tions to campaigns against schistosomal infestation conducted in 1920-1970, in
which parenteral medications were given under non-sterile conditions 25.
Primary liver cancer in different ethnic and migrant populations
In the US, lower incidence rates of primary liver cancer are found in the non-
Hispanic white population (2.3 to 3.0 in men and 1.1 to 3.1 in women) than in other
ethnic populations (Table 3). Among men, relatively high AAIRs are found in white
Hispanic (4.5-6.7), black (3.2-8.1), Japanese (5.8), American Indian (10.6), Filipino
(9.5-11.0), Chinese (16.1-20.5) and Korean (23.9) ethnic populations. Among
women, these high-risk groups present two- to five-fold higher primary liver cancer
AAIRs than the rates observed in non-Hispanic white women. In New Zealand,
different primary liver cancer AAIRs are found between Maori (12.8 in men and 3.6
in women) and non-Maori (2.9 in men and 3.1 in women) populations 2. The
HBsAg prevalence in Maori patients with primary liver cancer is 77%, compared to
6% for white New Zealanders with primary liver cancer; this difference could explain
the primary liver cancer AAIRs excess among Maoris 26. Similar results have been
found in the US, where HBsAg prevalence in primary liver cancer cases is higher for
Asian patients born in the US (80%) than for white patients with primary liver cancer
(19%) 27.
Migrant studies have been instrumental in the evaluation of the relative contri-
butions of environmental and genetic factors in primary liver cancer 28, usually
Table 3
Age-adjusted incidence rates of primary liver cancer per 105 in the USA by ethnic groups 1988-92 2.
Geographic area Non- Hispanic American Black Chinese Japanese Filipino Korean
Hispanic White Indian
White
MEN
California
Central Valley 2.7 5.4 - -
LosAngeles County 2.9 6.5 - 5.1 16,1 5.8 9.5 23.9
S. Francisco Bay Area 3.0 6.7 - 8.1 205 5.7 11.0 -
New Mexico 2.3 4.5 10.6 -
Connecticut 3.3 - 6.9
Georgia, Atlanta 3.0 - 3.2
Louisiana
Central region 2.1 - 5.0
New Orleans 3.6 7.9
Michigan, Detroit 3.1 - 7.0
WOMEN
California
Central Valley 1.3 3.4 - -
Los Angeles County 1.1 2.2 - 2.2 4.4 3.3 3.5 5.5
S. Francisco Bay Area 1.2 2.5 - 2.1 6.0 2.1 4.2 -
New Mexico 1.1 2.1 2.2 -
Connecticut 1.1 - 1.4
Georgia, Atlanta 1.0 - 1.6
Louisiana
Central region 1.3 - 0.8
New Orleans 1.0 - 2.2
Michigan, Detroit 1.3 - 2.4
using the population of the host country as the reference. Among migrant men from
Asia, a 5.2 to 10.5 excess primary liver cancer mortality has been observed; a 31.6-fold
excess has been observed among migrants from west Africa and a five-fold excess
among migrants from the Caribbean. Among migrant women the results have not
been so consistent, with an excess primary liver cancer mortality among migrant
women ranging from two- to five-fold 29-34 (Table 4).
Some of these studies have demonstrated that the risk of dying from primary liver
cancer decreases in the migrants living for a long time in the host country and among
the migrant's descendants. King and Lucke 35 estimated the risk of dying from
primary liver cancer in two generations of Asian migrants to the US; excess mortality
rates due to primary liver cancer were 10.9 in the first generation and 2.8 in the
second generation among men and 5.2 and 1.2 among women. A study conducted in
Australia found a substantial reduction of the risk of dying from primary liver cancer
among east and south-east Asian migrants according to duration of residence: 1.21
Table 4
Relative risks of primary liver cancer in migrant populations compared to host populations 29-34
Region of Origin and Host region Study RR RR RR both
Reference period men women sexes
China
Smith (1956) US including Hawaii 1949-52 3.3* - -
King (1973) US including Hawaii 1950-62 6.2* 1.1 -
Fraumeni (1974) US 1950-69 *7.9 4.3* -
Gallagher (1979) British Columbia, Canada 1964-73 7.7* 5.2 -
King (1980) California, Hawaii, NY City 1968-72 "9.01 5.2* -
Zhang (1984) New South Wales, Australia 1969-78 5.2* 2.6 -
Wang (1989) Canada 1980-84 10.5" 3.0* -
Fang (1996) New York City 1988-92 3.4* 2.4* -
East and Southeast Asia
Bouchardy (1994) France 1979-85
East Asia a 3.1 3.3* -
Southeast Asia b *5.2 "6.1 -
McCredie (1999) New South Wales, Australia 1975-95
East Asia c - - *9.8
Southeast Asia d - - "0.01
Near East e
Khlat (1993) Australia 1969-83 2.5* 3.0
Africa & Caribbean
Grulich (1992) England & Wales 1970-85
West African f 31.6" 5.4*
East Africang 1.1 8.1
Caribbean h 5.3* *2.3
aEast Asia: migrants born in the People's Republic of China, Taiwan and Hong Kong; bSoutheast Asia:
Vietnam, Cambodia and Laos; tsaEC Asia: China, Hong Kong, Japan, Korea and Taiwan; dSontheast Asia:
Myanmar, Cambodia, Indonesia, Laos, Malaysia, Philippines, Singapore, Thailand and Vietnam; °Near
East: Syria, Lebanon, Turkey, Egypt and Israel; fWest Africa: Sierra Leone, Ghana, Nigeria, Gambia;
gEast Africa: Kenya, Malawi, Tanzania, Uganda, Zambia; hCaribbean: Barbados, Trinidad, Tobago, West
Indies associated states, West Indies (so stated), Belize, Guyana, other Commonwealth Caribbean.
RR = Relative Risk; *Significantly different from RR=I or 95% confidence intervals exclude .1
for 0-9 years of residence, 11.9 for 10-19 years, 5.0 for 20-29 years and 1.3 for more
than 30 years 32. In the US, similar results have been observed 36.
In another US study, AAIRs in Chinese, Japanese and Filipino migrants to the
US and their descendants were compared to primary liver cancer AAIRs of US-born
whites. Rates for primary liver cancer were consistently higher for Asian men born in
Asia than in Asian men born in the US (second generation or later) as follows:
Chinese born in China: 26.5; Chinese born in the US: 9.8; Japanese born in Japan:
16.5; Japanese born in the US: 6.6; Filipinos born in the Philippines: 11.4 and
Filipinos born in the US: 6.5. The comparison incidence rate for US whites was 3.4.
Among women, the trends were not so consistent; Asian-born and US-born women
Table 5
Risk factors for primary liver cancer and estimates of the attributable fractions (%) 39,41-45,49,51-57
Risk factors Europe and the US Japan Africa and Asia
Estimate Range Estimate Range Estimate Range
Hepatitis B virus 22% 4-58% 20% 18-44% 60% 40--90%
Hepatitis C virus a 60% 12-72% 63% 48-94% 20% 9-56%
Alcohol 45% 8-57% 20% 15-33% - 11-41%
Tobacco 12% 0-14% 40% 9-51% 22% h -
Oral contraceptives - 10-50% c NE - 8% d -
Aflatoxin limited exposure limited exposure important exposure ~
Other <5% - - - <5% -
~Not including double infections with HBV and HCV; bestimates for HBsAg-negative black men;
Crestricted to liver cancer in women; ~ restricted to liver cancer in black women; °attributable risk not
quantified
NE: not evaluated.
Note: attributable fractions do not necessarily add up to 100% because of multiple exposures and possible
interactions between risk factors.
showed incidence rates as follows: Chinese: 2.2 and 3.7; Japanese: 1.9 and 1.4;
Filipino: 2.6 and 0; and US whites: 1.1 36.
Risk factors for liver cancer
Table 5 shows current estimates of the attributable fractions (AF %) for the main risk
factors for primary liver cancer arranged by broad geographic areas.
Hepatitis viruses
Overall, 75-80% of the primary liver cancer cases can be related to persistent viral
infections with either HBV (50-55%) or HCV (25-30%). Worldwide, strong
geographical correlations have been found between the incidence of primary liver
cancer and the prevalence of HBsAg (correlation coefficient: 0.67, p < 0.001) or
anti-HCV (correlation coefficient: 0.37,p < 0.001) (Figs. 2-4) 7 (Table 6). A large
study in Europe found that among primary liver cancer cases that were negative for
HBsAg and anti-HCV, an additional 33% were positive for HBV DNA and 7%
positive for HCV RNA 37. This observation has been repeatedly confirmed and the
trend suggests that in countries where HBV is common, the presence of HBV DNA
among HBsAg-negative primary liver cancer cases is consistently higher in low
prevalence areas such as Europe. Meta-analysis of viral factors and primary liver
cancer revealed summary Odds Ratios (OR) of 22.5 (95% C.I.: 19.5-26.0) for HBsAg
without anti-HCV or HCV RNA. The OR for anti-HCV or HCV RNA without
HBsAg was 17.3 (95% C.I.: 13.9-21.6), and the OR for all of these markers being
positive was 165 (95% C.I.: 81.2-374); this suggested a synergism of the two viruses in
the causation of primary liver cancer 38,39.